Olaparib and Temozolomide in Treating Patients with Recurrent Small Cell Lung Cancer

Status: Active

Description

This phase I / II trial studies the side effects and best dose of olaparib and temozolomide and to see how well they work in treating patients with small cell lung cancer that has come back (recurrent). Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving olaparib and temozolomide may be a better treatment for recurrent small cell lung cancer.

Eligibility Criteria

Inclusion Criteria

  • Participant must have histologically or cytologically confirmed small cell lung cancer and may not be a candidate for potentially curative therapy
  • Presence of measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1): at least one lesion, not previously irradiated, that can be accurately measured at baseline as >= 10 mm in the longest diameter (except lymph nodes which must have short axis >= 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements
  • The small cell lung cancer must have progressed radiographically following a platinum-based (cisplatin and/or carboplatin) standard prior chemotherapy regimen; any number of interval prior lines of therapy is allowed; patients who have received prior platinum-based chemotherapy and radiation for limited stage SCLC and have subsequently developed relapsed disease are eligible, as long as the platinum-based therapy was given within 12 months prior to the time of relapse
  • Hemoglobin >= 10.0 g/dL and no known active bleeding (within 28 days prior to administration of study treatment)
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 28 days prior to administration of study treatment)
  • White blood cells (WBC) > 3 x 10^9/L (within 28 days prior to administration of study treatment)
  • Platelet count >= 100 x 10^9/L (within 28 days prior to administration of study treatment)
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 days prior to administration of study treatment)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (unless liver metastases are present in which case it must be =< 5 x ULN) (within 28 days prior to administration of study treatment)
  • Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) (within 28 days prior to administration of study treatment)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Participant must have a life expectancy >= 16 weeks
  • Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days of initial dose of olaparib and temozolomide AND must agree to the use of two highly effective forms of contraception throughout their participation in the study and for at least 3 months after the last dose of olaparib and temozolomide, OR confirmed prior to treatment on day 1 to be postmenopausal or surgically sterile; postmenopausal is defined as: * Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments * Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the postmenopausal range for women under 50 * Radiation-induced oophorectomy with last menses > 1 year ago * Chemotherapy-induced menopause with > 1 year interval since last menses, or surgical sterilization (bilateral oophorectomy or hysterectomy)
  • Participant is willing to comply with the protocol for the duration of the study, and undergo treatment and scheduled visits and examinations including follow up
  • Participant must obtain prior approval from insurance to reimburse for oral temozolomide for the duration of the study or agree to self-pay for oral temozolomide

Exclusion Criteria

  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  • Previous enrollment in the present study
  • Participation in another clinical study with an investigational product during the 21 days prior to first dose of olaparib and temozolomide
  • Participants receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 2 weeks from the last dose prior to study treatment (or a longer period depending on the defined characteristics of the agents used); the patient can receive a stable dose of bisphosphonates for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment with olaparib and temozolomide
  • Participants are to discontinue the use of the following classes of inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4); patients who are on these drugs are eligible if a washout period of a minimum of 7 days occurs before start of olaparib and temozolomide: * Azole antifungals * Macrolide antibiotics * Protease inhibitors
  • Persistent clinically significant toxicities (>= CTCAE version [v.] 4.0 grade 2) caused by previous cancer therapy, with the exception of alopecia
  • Participants with a previously documented diagnosis of myelodysplastic syndrome (MDS) (or any dysplastic leukocyte morphology suggestive of MDS) or acute myeloid leukemia
  • Participants with symptomatic uncontrolled brain metastases; baseline brain imaging by CT or MRI is required for all patients; participants with brain metastases that have been treated with prior radiation therapy and are stable on a subsequent scan are allowed; participants with untreated possible brain metastases that are new at the time of screening and are < 1 cm and asymptomatic are allowed; the participant can receive corticosteroids as long as these were started and at a stable dose at least 28 days prior to treatment
  • Major surgery within 14 days of starting study treatment and patients must have recovered from any effects of any major surgery
  • Participants considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection; examples include, but are not limited to, corrected QT interval (QTc) prolongation > 470 msec, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord compression (untreated and unstable for at least 28 days prior to study entry), extensive bilateral lung disease with less than 20% predicted lung function by carbon monoxide diffusing capability test (DLCO) (lung diffusion capacity testing), or any psychiatric disorder that prohibits obtaining informed consent
  • Participants unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
  • Pregnant or breast feeding women; all patients (male and female) must agree to practice a medically acceptable method of contraception; should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately
  • Patients who have a history of and are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy; baseline testing is not required
  • Patients with known active hepatitis B or C; baseline testing is not required
  • Patients with a known hypersensitivity to olaparib, temozolomide or any of the excipients of the products
  • Patients with uncontrolled seizures
  • Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for >= 5 years
  • Patients with current and symptomatic pneumonitis, or extensive bilateral lung disease on high resolution CT scan
  • Patients with whole blood transfusion in the last 120 days prior to entry to the study
  • Patients with previous allogeneic bone marrow transplant
  • Patients with active, uncontrolled infection
  • Patients who need to continue treatment with any prohibited medications
  • Patients who have not completed the appropriate washout period for the prohibited medications

Locations & Contacts

Massachusetts

Boston
Beth Israel Deaconess Medical Center
Status: Active
Contact: Deepa Rangachari
Phone: 617-667-1580
Email: drangach@bidmc.harvard.edu
Brigham and Women's Hospital
Status: Active
Contact: Anna F. Farago
Phone: 617-724-4000
Email: afarago@mgh.harvard.edu
Dana-Farber Cancer Institute
Status: Active
Contact: David Allen Barbie
Phone: 617-632-6049
Email: dbarbie@partners.org
Massachusetts General Hospital Cancer Center
Status: Active
Contact: Anna F. Farago
Phone: 617-724-4000
Email: afarago@mgh.harvard.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of combined oral administration of olaparib and TMZ (temozolomide) with intermittent dosing of both drugs (cohort 1) and with continuous dosing of olaparib and intermittent dosing of TMZ (cohort 2) in patients with recurrent small cell lung cancer (SCLC). (Phase I)

II. Determine the overall response rate (ORR) to combination olaparib and TMZ with intermittent dosing of both drugs (cohort 1) and with continuous dosing of olaparib and intermittent dosing of TMZ (cohort 2) in patients with recurrent SCLC. (Phase II)

SECONDARY OBJECTIVES:

I. Evaluate the safety and tolerability of combination olaparib and TMZ as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. (Phase I)

II. Explore variations in O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase gene (MGMT) promoter methylation status and poly-adenosine diphosphate (ADP)-ribose (PAR) levels in tumor biopsy samples obtained before and during treatment. (Cohort 1 only) (Phase I)

III. Evaluate the safety and tolerability of combination olaparib and TMZ as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. (Phase II)

IV. Measure the time of progression free survival (PFS), and overall survival (OS) in response to olaparib and TMZ therapy. (Phase II)

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study. Patients are assigned to 1 of 2 cohorts.

COHORT 1: Patients receive olaparib orally (PO) twice daily (BID) and temozolomide PO once daily (QD) on days 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

COHORT 2: Patients receive olaparib PO BID on days 1-21 and temozolomide PO QD on days 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 3 months.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Anna F. Farago

Trial IDs

Primary ID 15-121
Secondary IDs NCI-2015-01724
Clinicaltrials.gov ID NCT02446704